Acyl amino pyridines

ABSTRACT

Novel N-(4-pyridyl)acetamide derivatives having the formula ##STR1## [where R 1  and R 2  are aryl or heteroarly (optionally linked together by a lower alkylene bridge) or one of R 1  and R 2  is aryl or heteroaryl and the other of R 1  and R 2  is lower alkyl or ar(lower)alkyl, R 3  and R 4  are each hydrogen or lower alkyl] and their nontoxic acid addition salts are described. They are chemical intermediates for the preparation of 4-pyridinamine derivatives having the formula ##STR2## which show CNS activity and may be used as antidepressant drugs.

This application is a division of application Ser. No. 51,100 filed June22, 1979, now abandoned, which is a continuation-in-part of applicationSer. No. 873,192 filed Jan. 30, 1978, now U.S. Pat. No. 4,180,670.

The invention relates to novel N-(4-pyridyl) acetamide derivativesuseful as chemical intermediates for the preparation of pharmaceuticallyactive 4-aminopyridine derivatives.

The invention provides novel compounds having the formula I ##STR3## andtheir acid addition salts, wherein R¹ and R² together represent -Ar¹-(lower alkylene)-Ar² - where Ar¹ and Ar² are independently arylene orheteroarylene, or when R¹ and R² are separate, one of R¹ and R²represents aryl or heteroaryl and the other one of R¹ and R² representsaryl, heteroaryl, ar(lower)alkyl or lower alkyl and R³ and R⁴ areindependently hydrogen or lower alkyl.

By the term "lower" as used herein in connection with such groups asalkyl, alkylene and alkoxy, there is meant that the group contains up to6 carbon atoms, preferably up to 4 carbon atoms. By the term "aryl orheteroaryl" there is meant a monovalent group having aromatic character.By the term "arylene or heteroarylene" there is meant a divalent grouphaving aromatic character. The groups having aromatic character may becarbocyclic or heterocyclic and the aromatic ring or rings may beunsubstituted or carry one or more substituents.

R¹ and R² may be the same or different aromatic groups. Examples of arylgroups include phenyl; naphthyl phenyl substituted by one or twosubstituents, for example, halogen, for instance, fluorine, chlorine orbromine; lower alkyl, for instance, methyl, ethyl, propyl or butyl;lower alkoxy, for instance methoxy, ethoxy, propoxy or butoxy; loweralkylenedioxy, for instance methylenedioxy and trihaloalkyl, forinstance, trifluoromethyl. The aryl group preferably has a monocyclicaromatic ring but may be bicyclic, for instance, naphthyl or naphthylcarrying one or more substituents, for example, those mentioned above inconnection with substitution of phenyl. Examples of heteroaryl groupsinclude furyl (for example, 3-furyl), thienyl (for example, 2-thienyl),oxazolyl, thiazolyl, benzthiazolyl, pyridyl (for example 2- and4-pyridyl), quinolyl (for example 2-quinolyl) and isothiazolyl (forexample, 5-isothiazolyl). The heteroaryl groups may be unsubstituted orsubstituted as described above for the substitution of phenyl. Preferredheteroaryl groups are thienyl, pyridyl and furyl.

One of R¹ and R² may be an aryl or heteroaryl group as described abovewhilst the other of R¹ and R² may be lower alkyl, for example, methyl,ethyl, propyl, butyl or pentyl, or ar(lower)alkyl, for instance,phen(lower)alkyl, e.g. benzyl or phenethyl. When R¹ and R² are connectedtogether the two arylene or heteroarylene groups may be the same ordifferent. The groups may be divalent groups corresponding to the aryland heteroaryl groups particularly described above, for instance,phenylene.

When R¹ and R² are linked together they may represent a divalent grouphaving the formula ##STR4## wherein A is alkylene of 1 to 4 carbon atomsand each of B₁ and B₂ together with the two carbon atoms attachedthereto independently represents arylene or heteroarylene. The dottedlines in formula II in the rings are intended to indicate the aromaticcharacter of the rings. The arylene and heteroarylene groups may bephenylene; phenylene substituted by one to two substituents selectedfrom halogen, lower alkyl, lower alkoxy, lower alkylenedioxy andtrifluoromethyl; naphthalene; pyridine-diyl and thiophene-diyl. Examplesinclude o-phenylene, o-phenylene substituted as aforesaid,thiophene-2,3-diyl or thiophene-3,4-diyl.

The alkylene group of 1 to 4 carbon atoms represented by A in formula IImay be a straight chain, for instance, methylene, dimethylene ortrimethylene or may be branched, for example, a group having the formula--C(CH₃)₂ --CH₂ --.

R³ and R⁴ may be the same or different and are selected from hydrogenand lower alkyl, for example, methyl, ethyl, propyl and butyl. R³ and R⁴are preferably chosen from hydrogen and methyl.

The acid addition salts may be formed from inorganic acids and organicacids and examples include the sulphate, hydrochloride, hydrobromide,hydroiodide, nitrate, phosphate, sulphonate (such as the methanesulphonate and toluene-p-sulphonate), acetate, maleate, fumarate,tartrate and formate.

It will be apparent to the reader that the compounds having formula Iwhere R¹ and R² differ possess an asymmetric carbon atom and thusexhibit the property of optical isomerism. The invention includes theindividual optical isomers as well as the racemic mixtures. Theracemates may be resolved into individual optical isomers in knownmanner.

The compounds of general formula I and their acid addition salts can beprepared in manner known per se. In particular an amine having theformula ##STR5## (where R³ and R⁴ are as defined above) is acylated tointroduce the acyl group ##STR6## (where R¹ and R² are as definedabove). The acylation may be performed using the acyl halide, forinstance, the acyl chloride or acyl bormide, in the presence of asuitable base. The starting materials for the acylation can be preparedby standard methods.

The compounds having formula I and their acid addition salts may bereduced so as to form 4-aminopyridine derivatives having the formula V##STR7## (wherein R¹, R², R³ and R⁴ are as defined above). The reductionmay be carried out under conditions known for the reduction of amides toform amines. As reducing agent there may be used lithium aluminiumhydride or diborane.

The compounds having formula V and their pharmaceutically acceptableacid addition salts are indicated for pharmaceutical use. In particularthey show CNS (central nervous system) activity, when tested on warmblooded animals. They reverse the hypothermia induced by reserpine onmice and thus may be used as antidepressent drugs. The reduction productof Example 1 was active in reversing hypothermia induced by reserpine inmice at a dose of 5 mg/kg p.o. and the reduction product of Example 2was active at 100 mg/kg p.o.

The following Examples illustrate the invention:

EXAMPLE 1 N-(2,2-diphenylethyl)4-pyridinamine

Diborane (generated from 0.033 moles NaBH₄ and 0.06 moles BF₃ /Et₂ O)was swept by a stream of nitrogen into a flask containing 2.16 grams(7.5 millimoles) of N-(4-pyridyl)diphenyl acetamide in 50 milliliters ofdry tetrahydrofuran stirred and cooled to 0° C. When all diborane hadbeen formed, the reaction mixture was heated under reflux for 3 hoursand then left overnight at room temperature. The mixture was cooled to0° C. and 10 millilitres of 6N hydrochloric acid was added. Thetetrahydrofuran was removed at atmosphere pressure. The product wasneutralised with 5N sodium hydroxide, extracted into ether, dried(MgSO₄) and evaporated to an oil which solidified. After triturationwith ether, 1.46 g (71% yield) of fine felted needles were obtained. Thetitle compound was converted to its hydrochloride by solution inisopropyl alcohol/HCl/Et₂ O. 1.18 Grams of product m.p. 205°-207°, wereobtained.

Analysis: Found C, 73.48%; H, 6.28%; N, 9.07%. C₁₉ H₁₈ N₂ HCl requiresC, 73.56%; H, 6.16%; N, 9.03%.

The N-(4-pyridyl)diphenylacetamide starting material was prepared asfollows:

9.4 Grams (0.1 mole) of 4-aminopyridine and 11.5 grams (0.05 mole) ofdiphenyl acetyl chloride were stirred together at room temperature in 65milliliters of pyridine for 4.5 hours. The resulting mixture was pouredinto water and extracted with toluene. The organic phase was separateddried (MgSO₄) and the toluene removed. The resulting solid wasrecrystallised from toluene yielding 10.9 g2,2-diphenyl-N-(4-pyridinyl)acetamide m.p. 166.5°-168° C. The fumaratesalt was prepared by dissolving equimolar quantities of the free baseand fumaric acid in hot 2-propanol and allowing the product tocrystallise. Melting point 171°-173° C. Analysis: Found C, 68.2%; H,5.25%; N, 6.7%. C₁₉ H₁₆ N₂ O.C₄ H₄ O₄ requires: C, 68.3%; H, 5.0%; N,6.7%.

EXAMPLE 2N-[(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)methyl]-4-pyridinamine

Diborane was generated by the dropwise addition over 11/2 hours at roomtemperature of a solution of 1.14 grams (30 millimoles) of sodiumborohydride in 30 c.c. of dry diglyme to a mixture of 6.2 c.c. (7.1grams, 50 millimoles) of redistilled boron trifluoride etherate and 6.2c.c. of dry diglyme. The evolved diborane was swept in a slow stream ofdry nitrogen into a solution of 3.14 grams (10 millimoles) ofN-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)carbonyl]-4-pyridinaminein 50 c.c. of dry tetrahydrofuran, cooled in ice. After completeaddition of the borohydride solution, the generator flask was heated to70°-80° for 1/2 hour to complete the generation of diborane, which wasswept into the reduction mixture as before. The reduction mixture wasstirred at 0° for a further hour and was then heated to reflux for 3hours, maintaining the nitrogen atmosphere. The apparatus was thensealed and allowed to cool overnight. 6 Milliliters of 6N hydrochloricacid were then added dropwise with care to the reduction mixture,resulting in vigorous hydrogen evolution. The acid solution was theevaporated to dryness to remove tetrahydrofuran and the residue wastreated with 25 c.c. of water, basified to pH9 with potassium carbonate,filtered, and the filtrate was extracted repeatedly withdichloromethane. The combined organic extracts were dried using MgSO₄and evaporated, leaving 3.02 grams of a yellow oil whose IR spectrumcontained no C═O absorption. This oil was taken up in a mixture ofpropan-2-ol, methanol and dichloromethane, made acid with etherealhydrogen chloride, filtered and concentrated to 15 c.c. On coolingN-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methyl]-4-pyridinamine,hydrochloride was deposited as colourless crystals (1.58 g, 42%), mp245°-6° with effervescence. Analysis: Found C, 75.0%; H, 6.3%; N, 8.1%.C₂₁ H₂₀ N₂.HCl requires C, 74.9%; H, 6.3%; N, 8.3% TheN-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)carbonyl]-4-pyridinaminestarting material was prepared as follows:

A solution of 4.7 grams (50 milliliters) of 4-aminopyridine in 50 c.c.of dry pyridine was treated dropwise at room temperature with a solutionof 6.6 grams of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylcarbonylchloride (M. A. Davis, Stanley O. Winthrop, J. Steward, F. A. Sunahara,and F. Herr, J. Medicin. Chem. 1963, 6, 251-5) in 50 c.c. of toluene.After the exothermic reaction subsided the mixture was stirred at roomtemperature for 4 hours and was then poured into 30 c.c. of water. 100milliliters of toluene were added and the phases were separated. Thetoluene phase was washed once with 100 c.c. of water, then the combinedaqueous phases were back-extracted with toluene (3×100 c.c.). Thecombined toluene solutions were dried (MgSO₄) and evaporated, leaving anoily residue which was evaporated several times with further toluene andfinally once with ethanol to remove residual pyridine, giving 8.45 gramsof a yellow solid. This solid was crystallised from toluene (charcoal)giving off-white crystals (4.78 g. 61%), mp 145°-6°; second crop,off-white crystals (0.96 g, 12%), mp 145°-7.5°.

Both crops were indicated by infrared spectroscopy to contain a trace ofcarboxylic acid (C═O at 1700 cm), so both fractions were combined,dissolved in toluene (150 c.c.) and washed with 2N sodium hydroxidesolution (3×25 c.c.) water (3×25 c.c.) and saturated sodium chloridesolution (2×25 c.c.), and dried (MgSO₄). The solution was filtered,concentrated to 50 c.c. and allowed to crystallise, giving 4.64 grams(57% yield) ofN-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)carbonyl]-4-pyridinamineas colourless crystals, mp. 148°-9°.

Analysis: Found C, 80.5%; H, 6.0%; N, 9.0%. C₂₁ H₁₈ N₂ O requires C,80.2%; H, 5.8%; N, 8.9%.

EXAMPLE 3

The following acyl chlorides are reacted with the following amines in amanner similar to Examples 1 and 2 to give the products indicated.

    ______________________________________                                        Acyl Chloride                                                                              Amine      Product                                               ______________________________________                                        Di(p-fluorophenyl)                                                                         2-Methyl-4-                                                                              2,2-Di(p-fluorophenyl)-                               acetyl chloride                                                                            pyridin-   N--(2-methyl-4-pyridyl)-                                           amine      acetamide                                             Di(m-trifluoro-                                                                            4-pyridin- N--(4-pyridyl)-2,2-di                                 phenyl)acetyl                                                                              amine      (m-trifluorophenyl)-                                  chloride                acetamide                                             (3,4-Dichloro-                                                                             4-pyridin- 2-(3,4-dichlorophenyl)-                               phenyl)phenyl                                                                              amine      2-phenyl-N--(4-pyridyl)-                              acetyl chloride         acetamide                                             2-Phenylbutyryl                                                                            4-Pyridin- 2-Phenyl-N--(4-pyridyl)-                              chloride     amine      butyramide                                            (β-Naphthyl)-                                                                         4-Pyridin- 2-(β-Naphthyl)-2-phenyl-                         (phenyl)acetyl                                                                             amine      N--(4-pyridyl)acetamide                               dibride                                                                       (p-Ethoxyphenyl)-                                                                          4-Pyridin- 2-(p-Ethoxyphenyl)-N--                                (m-toluyl)acetyl                                                                           amine      (4-pyridyl)-2-(m-toluyl)                              chloride                acetamide                                             (3,4-Methylenedioxy-                                                                       N--methyl- N--Methy1-2-(3,4-                                     phenyl)phenyl                                                                              4-pyridin- methylenedioxyphenyl)-                                acetyl chloride                                                                            amine      2-phenyl-N--(4-pyridyl)                                                       acetamide                                             (Phenyl)2-thienyl)                                                                         4-Pyridin- 2-Phenyl-N--(4-pyridyl)-                              acetylchloride                                                                             amine      2-(2-thienyl)acetamide                                (Phenyl)(2-pyridyl)                                                                        4-Pyridin- 2-Phenyl-2-(2-pyridyl)-                               acetyl chloride                                                                            amine      N--(4-pyridyl)acetamide                               5,6,7,12-Tetrahydros-                                                                      4-Pyridin- N--[5,6,7,12-tetrahydro-                              dibenzo[a,d]cyclo-                                                                         amine      dibenzo[a,d]-cycloocten-                              octen-12-ylcarbonyl     12-yl)carbonyl]-4-                                    chloride                pyridinamine                                          10,11-Dihydro-10,10-                                                                       2-Methyl-4-                                                                              N--(10,11-Dihydro-10,10-                              dimethyl-5H--benzo-                                                                        pyridin-   dimethyl-5H--benzo[a,d]                               [a,d]cyclohept-5-                                                                          amine      cyclohept-5-yl)carbonyl]- -ylcarbonyl                                         chloride  2-methyl-4-pyridinamine                     4,9-Dihydro-naphtho                                                                        N--methyl-4-                                                                             N--[(4,9-Dihydro-naphtho                              [2,3-c]thien-4-                                                                            pyridin-   [2,3-c]-thien-4-yl)                                   ylcarbonyl chloride                                                                        amine      carbonyl]-N--methyl-4-                                                        pyridinamine                                          5,10-Dihdro-benzo                                                                          4-Pyridin- N--[5,10-dihydro-benzo                                [g]quinol-10-                                                                              amine      [g]quinol-10-yl)                                      ylcarbonyl chloride     carbonyl]-4-pyridin-                                                          amine                                                 7,12-Dihydro-                                                                              4-Pyridin- N--[(7,12-dihydro-benz                                benz[a]anthracen-                                                                          amine      [a]anthracen-7-yl)                                    7-ylcarbonyl chloride   carbonyl]-4-pyridinamine                              10,11-Dihydro-1-                                                                           4-Pyridin- N--[(10,11-dihydro-1-                                 methyl-5H--dibenzo                                                                         amine      methyl-5H--dibenzo[a,d]                               [a,d]cyclohepten-       cyclohepten-5-yl)                                     5-ylcarbonyl            carbonyl]-4-pyridinamine                              chloride                                                                      10,11-Dihydro-2,3-                                                                         4-Pyridin- N--[(10,11-dihydro-2,3-                               dimethoxy-5H--                                                                             amine      dimethoxy-5H--di-                                     dibenzo[a,d]cyclo-      benzo[a,d]cyclohepten-                                hept-5-ylcarbonyl       5-yl)carbonyl]-                                       chloride                4-pyridinamine                                        10,11-Dihydro-2,3-                                                                         4-Pyridin- N--[(10,11-dihydro-2,3-                               methylenedioxy-5H--                                                                        amine      methylenedioxy-                                       dibenzo[a,d]cyclo-      5H--dibenzo                                           hept-5-ylcarbonyl       [a,d]cyclohept-5-yl)                                  chloride                carbonyl]-4-pyridinamine                              10,11-Dihydro-3-                                                                           4-Pyridin- N--[10,11-dihydro-3-tri-                              trifluoromethyl-                                                                           amine      fluoromethyl-5H--dibenzo                              5H--dibenzo[a,d]        [a,d]cyclohept-5-yl)                                  cyclohept-5-yl          carbonyl]-4-pyridinamine                              carbonyl chloride                                                             ______________________________________                                    

We claim:
 1. A compound selected from those having the formula ##STR8##and their pharmaceutically acceptable acid addition salts, wherein R¹and R² together represent a divalent group having the formula ##STR9##wherein A is alkylene of 1 to 4 carbon atoms and each of B₁ and B₂together with the two carbon atoms attached thereto represents a memberselected from the group consisting of phenylene; naphthylene; phenylenesubstituted by one to two substituents selected from halogen, loweralkyl, lower alkoxy, lower alkylenedioxy and trifluoromethyl;pyridinediyl and thiophene-diyl, and R³ and R⁴ are independentlyselected from hydrogen and lower alkyl.
 2. A compound as defined inclaim 1, which isN-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)carbonyl]-4-pyridinamineor a pharmaceutical acceptable acid addition salt thereof.